Dithienylalkylamines and process for their production

ABSTRACT

There are prepared compounds of the formula ##STR1## where &gt;A--B-- has either the structure &gt;C(OH)--CH 2  -- or the structure &gt;C═CH, Alk is a straight or branched chain C 1  -C 5  - alkylene group and -NHY is ##STR2## where R&#39; is hydrogen, phenyl, phenyl substituted once or twice by C 1  -C 4  -alkyl groups, a C 1  -C 4  -alkoxy group or by halogen atoms, a C 1  -C 6  -alkyl group, a C 1  -C 4  -hydroxyalkyl group or a phenalkyl group whose alkyl portion consists of 1-4 carbon atoms or such a phenalkyl group containing 1 to 3 C 1  -C 4  -alkoxy group substituents. The compounds are effective in improving peripheral and cerebral circulation. There are also produced intermediate compounds of formula (II) where NHY is replaced by chlorine, bromine or iodine.

BACKGROUND OF THE INVENTION

Compounds corresponding to the general formula ##STR3## in which R₁, R₂and R₅ each represent a hydrogen atom or a methyl group, R₃ represents ahydrogen atom or a hydroxyl group, R₄ represents a hydrogen or chlorineor fluorine atom or a trifluoromethyl group or an alkyl group with 1 to6 carbon atoms or an alkoxy group with 1 to 6 carbon atoms and thebridge member >A--B-- has the structure >C(OH)--CH₂ -- or >C═CH--, arealready known. They are particularly effective in improving cerebralcirculation.

These compounds can be produced by a process in which a compoundcorresponding to the general formula ##STR4## in which Y is chlorine orbromine or an alkoxy group or a thienyl radical, is reacted with athienyl metal compound (thienyl lithium, thienyl Grignard compound) andcompounds of the general formula in which >A--B-- is the group>C(OH)--CH₂ --, are optionally converted with a dehydrating agent intothe corresponding unsaturated compounds (>A--B--:>C═CH--) by knownmethods and the basic compounds obtained are optionally converted intothe salts by known methods (Thiele German Patent No. 1,921,453 andrelated but not identical Thiele U.S. Pat. No. 3,766,173. The entiredisclosure of the Thiele U.S. patent is hereby incorporated by referenceand relied upon.).

However, it is not possible by this process to produce any compounds inwhich the phenyl radical in the above formula is substituted by ahydroxy group or in which the amine portion is derived from structurallydifferent amines.

Furthermore, there are known compounds of the following formula ##STR5##

In the just given formulae R₆ and R₇ represent hydrogen or a methylgroup and both R₈ are, C₁ -C₄ -alkyl groups or one R₈ is hydrogen andthe other is a benzyl group or the entire group --NR₈ R₈ forms apyrrolidino group, a piperidino group, a morpholino group or ahomopiperidino group. There is stated as the main activity for thesecompounds a spasmolytic activity (Chimie Therapeutique (1973) pages22-31).

SUMMARY OF THE INVENTION

The invention is directed to other new compounds of the formula ##STR6##where >A--B-- has either the structure >C(OH)--CH₂ -- or thestructure >C═CH, Alk is a straight or branched chain C₁ -C₅ -alkylenegroup and Y is a C₃ -C₇ -cycloalkyl group, a benzyl group, amethylenedioxybenzyl group, a benzyl group having one, two or three C₁-C₄ -alkyl or C₁ -C₄ -alkoxy group substituents, a C₁ -C₆ -alkyl group,or a C₁ -C₆ -alkyl group substituted by an amino group, a di C₁ -C₄-alkylamino group, a mono C₁ -C₄ -alkylamino group, a morpholino group,a piperazino group or a 4-(C₁ -C₄ -alkyl)-piperazino group, or Y is##STR7## where R is hydrogen or a C₁ -C₄ -alkyl group and T is hydrogenor a C₂ -C₆ -alkanoyl group (e.g., acetyl, propionyl, hexanoyl) or where--NHY is ##STR8## where R' is hydrogen, phenyl, phenyl substituted onceor twice by C₁ -C₄ -alkyl groups, a C₁ -C₄ -alkoxy group or by halogenatoms (e.g., fluorine, chlorine or bromine), a C₁ -C₆ -alkyl group, a C₁-C₄ -hydroxyalkyl group or a phenalkyl group whose alkyl portionconsists of 1-4 carbon atoms or such a phenalkyl group containing 1 to 3C₁ -C₄ -alkoxy group substituents or wherein the group --NHY ismorpholino, piperidino or when Alk has 2 to 5 carbon atoms a di-C₁ -C₄-alkylamino group or the group --NH--CH(R)--CH(OH)--C₆ H₅ and saltsthereof, preferably a pharmaceutically acceptable salt.

The two thienyl radicals are preferably attached to A--B-- in the sameposition (bis-thienyl-(3) or bis-thienyl-(2) derivatives). However, itis also possible that A--B-- is simultaneously attached to a thienyl-(2)and a thienyl-(3) group. The group R in the structural part ##STR9## ispreferably methyl or ethyl. The hydroxy group on the phenyl ring can bein the ortho, para or meta position. In case this is acylated thestarting C₂ -C₆ aliphatic carboxylic acid can be straight or branchedand especially can consist of 2-4 carbon atoms, e.g., acetyl, propionyl,butyryl, isobutyryl. The alkylene chain Alk is preferably straight andpreferably consists of 1, 2 or 3 carbon atoms.

Y is preferably the group ##STR10## where R' is as defined above;preferably R' is phenyl or a phenyl substituted by a C₁ -C₂ -alkyl group(for example methyl or ethyl) or a C₁ -C₂ -alkoxy group (OCH₃, OC₂ H₅).Preferably the substituent is in the ortho position. In case R' is aphenalkyl group, it is especially the benzyl or phenethyl group, in agiven case substituted by 1 or 2 methoxy groups.

In addition to the compounds set forth in the working examples below,other illustrative examples of compounds within the invention include

[1,1-(dithienyl-(3)-1-hydroxyamyl-(5)]-[1-hydroxy-1-(p-hydroxyphenyl)-propyl-(2)]-amine;

[1,1-dithienyl-(2)-1-hydroxypropyl-(3)]-[1-hydroxy-1-(p-hydroxyphenyl)-propyl-(2)]-amine;

[1,1-dithienyl-(2)-1-propenyl-(3)]-[1-hydroxy-1-(p-hydroxyphenyl)-propyl-(2)]-amine

as well as compounds of the formula ##STR11## in the following table

    ______________________________________                                        NHY                                                                           NHcycloheptyl                                                                  ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                    NHC.sub.6 H.sub.13                                                            NHCH.sub.2 CH.sub.2 NH.sub.2                                                  NHCH.sub.2 NH.sub.2                                                           NHCH.sub.2 CH.sub.2 NH.sub.2                                                  NH(CH.sub.2).sub.6 NH.sub.2                                                   NH(CH.sub.2).sub.3 NHCH.sub.3                                                 NH(CH.sub.2).sub.3 NHC.sub.2 H.sub.5                                          NH(CH.sub.2).sub.4 NHC.sub.4 H.sub.9                                           ##STR20##                                                                     ##STR21##                                                                     ##STR22##                                                                    NH(CH.sub.2).sub.2 NHi-C.sub.3 H.sub.7                                         ##STR23##                                                                     ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                     ##STR29##                                                                     ##STR30##                                                                     ##STR31##                                                                     ##STR32##                                                                     ##STR33##                                                                     ##STR34##                                                                     ##STR35##                                                                     ##STR36##                                                                     ##STR37##                                                                     ##STR38##                                                                     ##STR39##                                                                     ##STR40##                                                                     ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                     ##STR44##                                                                     ##STR45##                                                                     ##STR46##                                                                     ##STR47##                                                                     ##STR48##                                                                     ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                     ##STR53##                                                                    ______________________________________                                    

While the compounds in the above table and in examples 1-7 arebis-thienyl-(3) derivatives, the corresponding bis-thienyl-(2)derivatives can be made simply by replacing the 3-bromo-thiophene by2-bromo-thiophene in the starting material as pointed out hereinafterand as shown in Thiele German Pat. No. 1921453.

The new compounds according to the invention of formula (I) showpharmacodynamic activity, especially in disorders of the heart andcirculation system. In particular, they produce an increase inperipheral and cerebral circulation and in this respect, for example,are considerably more active, especially in regard to peripheralcirculation, than the known compounds according to Thiele German patent1,921,453. In some cases, the compounds according to the invention alsodilate the coronary arteries and increase the power of the heart.

The compounds of general formula (I) are produced by condensing acompound corresponding to the general formula ##STR54## in which Alk isa straight or branched chain C₁ -C₅ -alkylene group and X representschlorine, bromine or iodine, with an amine corresponding to the generalformula

    H.sub.2 NY                                                 (III)

in which Y is as defined above, and optionally converting compoundscorresponding to general formula (I), in which >A--B--═>C(OH)--CH₂ --,into the corresponding unsaturated compounds (>A--B--═>C═CH--) with adehydrating agent by known methods and/or acylating with an aliphatic(e.g., alkanoic) C₂ -C₆ carboxylic acid and optionally producing thesalts from the basic compounds obtained.

This condensation reaction is carried out, for example, in the presenceor absence of a solvent and at a temperature in the range from 0° to+150° C. and preferably at a temperature in the range from 20° to 100°C. Suitable inert solvents or suspending agents are, for example,saturated ethers, such as lower aliphatic dialkyl ethers, e.g., diethylether, dipropyl ether, dibutyl ether, alkyl ethers of cycloalkanols andalkyl-substituted cycloalkanols, e.g., methyl cyclohexyl ether, ethylcyclohexyl ether; saturated liquid hydrocarbons, e.g., pentane, hexane,octane, decane, petroleum ether, saturated cycloaliphatic hydrocarbonswhich may even be substituted by lower alkyl radicals, e.g.,cyclohexane, decahydronaphthalene, methyl cyclohexane, cyclic ethers,such as tetrahydrofuran and dioxane; benzene; alkyl benzenes such astoluene and xylene; aliphatic saturated ketones, e.g., acetone, methylether ketone; aliphatic and cycloaliphatic alcohols, e.g., methylalcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, cyclohexanol.The concentration of compound II in the solvent or suspending agentamounts for example to between 10 and 50%. The condensation reactionwith compound III is best carried out in the presence of a base orhydrogen halide acceptor, such as, for example, tertiary amines (e.g.,triethylamine, dimethyl aniline, tributyl amine), alkali metalcarbonates (potash or sodium carbonate), alkali metal hydroxides, e.g.,sodium hydroxide, potassium hydroxide. It is even possible to usecompound III itself as hydrogen halide acceptor. The condensationreaction takes place with advantage in a stoichiometric ratio, althoughit is also possible to use any excess of compound III. The reaction timeis governed by the reaction temperature. At temperatures in the rangefrom 100° to 120° C. for example, the reaction is over in 4 to 12 hours.

The elimination of water from compounds corresponding to general formula(I), in which >A--B--=>C(OH)--CH₂ --, is best carried out at elevatedtemperatures, for example, at a temperature in the range from 20° to150° C. It is preferred to use a solvent such as, for example, dialkylethers (such as those mentioned above), dioxane, glacial acetic acid,benzene, toluene, ethanol, isopropanol and so on.

For carrying out this dehydrating reaction, there is no need initiallyto isolate the compound of formula (I), in which >A--B-- represents thegroup >C(OH)--CH₂ --, instead the reaction mixture obtained after thereaction of compound II with compound III may for example be directlytreated with the dehydrating agent, optionally after removal of thesolvent. For example, isopropanolic or ethanolic hydrochloric acid maybe directly added to the reaction mixture which is then heated for a fewminutes to boiling point to obtain dehydration. The reaction product maybe worked up in the usual way.

Suitable dehydrating agents are, for example, mineral acids such assulfuric acid or hydrohalic acids, e.g., hydrochloric acid orhydrobromic acid; organic acids, such as oxalic acid, formic acid,thionyl chloride; aluminum chloride; zinc chloride; tin chloride; borontrifluoride; potassium hydrogen sulfate; phosphorus pentoxide; acidchlorides, e.g., acetyl chloride; red phosphorus-iodine in the presenceof water.

If compounds having the structural part ##STR55## are to be obtainedthen optionally the hydroxy group on the phenyl ring can be subsequentlyacylated by a C₂ -C₆ alkanoyl group.

The acylation can take place in an inert solvent or suspension agentsuch as dioxane, dimethyl formamide, benzene or toluene at temperaturesbetween 0° and 200° C. As acylating agents there can be used aliphaticC₂ -C₆ ketenes (e.g., ketene, methyl ketene, ethyl ketene, diethylketene) as well as acid halides, acid anhydrides or acid esters ofaliphatic carboxylic acid (e.g., alkanoic acids) of 2 to 6 carbon atoms,e.g., acetyl chloride, acetyl bromide, propionyl chloride, butyrylchloride, hexanoul chloride, acetic anhydride, butyric anhydride,optionally with an acid binding agent such as potassium carbonate,sodium carbonate or sodium ethylate or a tertiary amine, for example,triethyl amine. With the esters there are particularly employed thosewith lower aliphatic alcohols, e.g., methyl acetate, ethyl acetate,butyl acetate, methyl propionate, methyl caproate. In the acylation itis also possible to proceed by first producing an alkali compound fromthe reacting compound of formula (I) having the hydroxyl group on thephenyl ring while it is reacted at a temperature between 0° and 150° C.with an alkali metal, alkali hydride or alkali amide (particularlysodium ot sodium compounds, e.g., sodium hydride, sodium amide) in aninert solvent such as dioxane, dimethyl formamide, benzene or tolueneand then to add the acylating agent.

In place of the mentioned acylating agents there can also be used otherchemically equivalent acylating agents (see for example also: L. F. andMary Fieser, "Reagents for Organic Synthesis," John Wiley and Sons,Inc., New York, 1967, Vol. 1, pages 1303-4 and Vol. 2 page 471). It isunderstood that acyl groups present in formula (I) also can again besplit off in known manner, for example, by hydrolysis in the presence ofacids, e.g., hydrochloric acid or sulfuric acid or basic materials,e.g., sodium hydroxide or potassium hydroxide, at a temperature between20° and 150° C.

Those compounds which contain asymmetrical carbon atoms and which aregenerally formed as racemates may be split up into the optically activeisomers by methods known per se, for example, by means of an opticallyactive acid. However, it is also possible to use optically active oreven diastereomeric starting materials of general formula (III) from theoutset, in which case a corresponding pure optically active form ordiastereomeric configuration is obtained as the end product.

In the case of amines of the formula H₂ N--CH(R)--CH(OH)C₆ H₅ which alsocan be substituted in the phenyl ring by hydroxy or C₂ -C₆ alkanoyloxythere can be used as starting materials those which are present in theerythro or threo configuration. The end products of formula (I) areobtained in free form or in the form of their salts, depending upon theprocess conditions and starting materials used. The salts of the endproducts may be converted back into the bases by methods known per se,for example, with alkali (e.g., sodium hydroxide or potassium hydroxide)or ion exchangers, e.g., anion exchange resins. Salts may be obtainedfrom the bases by reaction with organic or inorganic acids, especiallythose which are suitable for the formation of therapeutically valuablesalts. Acids such as these are, for example, hydrohalic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, acids of phosphorus,e.g., phosphoric acid, phosphorous acid, nitric acid, perchloric acid,organic mono-, di- or tri-carboxylic acids of the aliphatic, alicyclic,aromatic or heterocyclic series, also sulfonic acids. Examples of theseacids are formic acid, acetic acid, propionic acid, butyric acid,succinic acid, oxalic acid, malonic acid, glycolic acid, lactic acid,malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid,fumaric acid, hydroxy maleic acid or pyruvic acid; phenyl acetic acid,benzoic acid, p-amino benzoic acid, anthranilic acid, p-hydroxy benzoicacid, salicyclic acid or p-amino salicylic acid, embonic acid, methanesulfonic acid, ethane sulfonic acid, hydroxyethane sulfonic acid,ethylene sulfonic acid; halogen benzene sulfonic acid, e.g.,p-chlorobenzenesulfonic acid, toluene sulfonic acid, naphthalenesulfonic acid or sulfanilic acid.

The compounds according to the invention are suitable for the productionof pharmaceutical compositions and preparations. The pharmaceuticalcompositions contain as active principle one or more of the compoundsaccording to the invention, optionally in admixture with otherpharmacologically active substances. The medicaments may be producedwith the usual pharmaceutical excipients and additives. The medicamentsmay be administered enterally, parenterally, orally, perlingually or inthe form of sprays. They may be made up in the form of tablets,capsules, pills, dragees, suppositories, liquids or aerosols. Suitableliquids are, for example, oily or aqueous solutions or suspensions.

The starting compounds of formula (II) are also new and, according tothe invention, are obtained by reacting thien-(3)-yl or thien-(2)-yllithium with a compound corresponding to the formula ##STR56## in whichAlk is a straight or branched C₁ -C₅ alkylene group, preferably astraight chain C₁ -C₃ -alkylene group and Z is a lower alkoxy group,e.g., 1-6 carbon atoms, chlorine, bromine, iodine or a thienyl radical,in an inert medium at a low temperature, preferably below -50° C. Thecompound of formula (II) is formed in a yield of, for example, 96% ofthe theoretical.

By contrast, hitherto known reactions of this type, for example ofthien-(3)-yl lithium with ω-phenyl-ethylaminopropionic acid esters (seeGerman Patent Specification No. 1,921,453) do not take place uniformlyand the required dithien-(3)-yl compound can only be isolated in yieldsof at most 30%. In particular, other thienyl isomers are always formedin relatively large quantities. In addition, separation of the requireddithienyl compound from the other reaction products and its purificationare extremely difficult and can only be carried out, for example, bycomplicated and elaborate recrystallization several times in combinationwith treatment with active carbon.

In general formula (IV), the radical Z is in particular a saturatedaliphatic alkoxy group with 1 to 6 carbon atoms, preferably with 1 to 4carbon atoms, which may even be branched, chlorine or bromine. However,Z can also be a thien-(2)-yl radical or a thien-(3)-yl radical.

The reaction of the thienyllithium compound, especially thien-(3)-yllithium, with compound IV takes place in an inert liquid solvent mixturewhich preferably consists of a saturated ether and a saturatedhydrocarbon and/or a benzene mono-substituted by C₁ -C₃ -alkyl radicals.

If the solvent mixture consists of an ether and a saturated hydrocarbon,from 0.3 to 3 parts by volume and preferably from 0.8 to 3 parts byvolume of ether are used for example to 1 part by volume of hydrocarbon.If the solvent mixture consists of ether and monoalkyl benzene, from 0.1to 3 parts by volume and preferably from 0.2 to 1 part by volume ofether are used for example to 1 part by volume of alkyl benzene. If thesolvent mixture at most 30%, in particular, other thienyl isomers arealways formed in relatively large quantities. In addition, separation ofthe required dithienyl compound from the other reaction products and itspurification are extremely difficult and can only be carried out, forexample, by complicated and elaborate recrystallization several times incombination with treatment with active carbon.

In general formula (IV), the radical Z is in particular a saturatedaliphatic alkoxy group with 1 to 6 carbon atoms, preferably with 1 to 4carbon atoms, which may even be branched, chlorine or bromine. However,Z can also be a thien-(2)-yl radical or a thien-(3)-yl radical.

The reaction of the thienyllithium compound, especially thien-(3)-yllithium, with the halogen C₂ -C₆ -alkane carboxylic acid ester takesplace at temperatures below -50° C. in an inert liquid solvent mixturewhich preferably consists of a saturated ether and a saturatedhydrocarbon and/or a benzene preferably from 0.8 to 3 parts by volume ofether are used for example to 1 part by volume of hydrocarbon. If thesolvent mixture consists of ether and monoalkyl benzene, from 0.1 to 3parts by volume and preferably from 0.2 to 1 part by volume of ether areused for example to 1 part by volume of alkyl benzene. If the solventmixture consists of the three components ether, saturated hydrocarbonand alkyl benzene, the ratio in which the three components ether,hydrocarbon and benzene are mixed is, for example,0.1-0.9:0.1-0.9:0.1-0.9. Suitable saturated ethers are, in particular,aliphatic symmetrical or asymmetrical dialkyl ethers, the alkyl groupspreferably consisting of 1 to 6 carbon atoms and being, for example,methyl, ethyl, isopropyl, propyl, isobutyl or butyl. Other suitableethers are, for example, C₁ -C₆ -alkyl ethers of saturated cycloalkanolsand the alkyl-substituted cycloalkanols, the cycloalkanol rings eachconsisting of 3, 4, 5 or 6 carbon atoms. The ethers are preferablyliquid at temperatures in the range from -80° to +20° C.

The saturated hydrocarbons are aliphatic or cycloaliphatic hydrocarbonswhich are liquid at temperatures in the range from -80° to +20° C. andwhich may contain for example from 5 to 9 and preferably 6 or 7 carbonatoms and may even be branched. The cycloaliphatic hydrocarbons arepreferably substituted once or even several times (twice, three times)by C₁ -C₄ -alkyl radicals, especially methyl, ethyl mono-substituted byC₁ -C₃ -alkyl radicals.

As halogenated carboxylic acid esters there can be used, for example,β-halogen propionic acid esters, γ-halogen butyric acid esters,Δ-halogen valeric acid esters, ε-halogen caproic acid esters, ω-halogenheptanoic acid esters.

In general formula (IV) above, the radical R represents in particular asaturated aliphatic alkyl group which 1 to 6 carbon atoms, preferablywith 1 to 4 carbon atoms, which may also be branched. Hal is preferablychlorine or bromine.

Examples of compounds of formula (IV) are ethyl 3-bromopropionate(3-bromopropionic acid ethyl ester), methyl 3-bromopropionate, propyl3-bromopropionate, isopropyl 3-bromopropionate, butyl 3-bromopropionate,hexyl 3-bromopropionate, amyl 3-bromopropionate, methyl3-chloropropionate, ethyl 3-chloropropionate, propyl 3-chloropropionate,isopeopyl 3-bromopropionate, butyl 3-chloropropionate, sec.butyl3-bromopropionate, hexyl 3-chloropropionate, methyl 3-iodopropionate,ethyl 3-iodopropionate, propyl 3-iodopropionate, butyl 3-iodopropionate,ethyl 4-chlorobutyrate, methyl 4-bromobutyrate, ethyl 5-bromovalerate,methyl 5-chlorovalerate, ethyl 5-chlorocaproate, methyl 5-bromocaproate,ethyl 5-bromoheptanoate, methyl 5-chloroheptanoate.

If the solvent mixture consists of an ether and a saturated hydrocarbon,from 0.3 to 3 parts by volume and or propyl radicals, the number of ringatoms amounting to 3, 4, 5, 6 or 7. The saturated alkyl radicals whichmay be used as substituents for the benzene are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.-butyl, 1-methyl propyl.

Examples of the solvents which may be used are diethyl ether,diisopropyl ether, methyl cyclopentyl ether, hexane, cyclohexane,toluene, xylene, methyl cyclohexane, methyl cyclopentane, ethylcyclohexane, dimethyl cyclohexane, methyl propyl ether, ethyl propylether, dimethyl ether, dihexyl ether, diamyl ether, dibutyl ether,dipropyl ether, diisobutyl ether, ethyl cyclohexyl ether, ethylcyclopropyl ether, methyl cyclobutyl ether, methyl ethyl cyclohexylether, ethyl methyl cyclohexyl ether, pentane, nonane, isoheptane,isooctane, octane, 2,3-dimethyl pentane, cyclopentane, ethylcyclopropane, methyl cycloheptane, butyl cyclohexane, isopropylcyclohexane, trimethyl cyclohexane, diethyl cyclopentane, isopropylbenzene, propyl benzene, butyl benzene, sec.butyl benzene, dibutylbenzene, dipropyl benzene.

It is of advantage to add compound IV (particularly if it is a β-halogenalkanoic acid ester, e.g., β-halogen propionic acid ester) as such or inthe form of a solution in the hydrocarbon and/or ether (for examplediisopropyl ether and/or toluene) to the thienyl lithium such asthien-(3)-yl lithium precooled to the reaction temperature and then tokeep the reaction mixture at the reaction temperature for about 1 to 4hours. Thereafter water for example is added to the reaction solution,optionally after heating to -20° to +20° C. The organic phase is dried(e.g., using MgSO₄ or NaSO₄) and concentrated by evaporation underreduced pressure. The crude 1,1-bis-[thien-(3 or 2)-yl]-3-halogenalkanol (e.g., propanol) thus obtained may be used without furtherpurification for the reaction with the amine NH₂ Y. The thienyl lithiumcompound, for example, thien-(3 or 2)-yl lithium is generally producedbeforehand from 2-bromo or 3-bromothiophene or from 2-iodo or3-iodothiophene in the ether and a C₁ -C₅ -alkyl lithium or aryl lithiumcompound in the ether/hydrocarbon mixture, the ethers and hydrocarbonsalready mentioned (including the alkyl benzenes) being suitable for thispurpose (a dialkyl ether being particularly preferred as the ethercomponent). The alkyl radical of the alkyl lithium compound may belinear or branched. Examples of suitable alkyl lithium compounds arebutyl lithium, sec.-butyl lithium, tert.-butyl lithium, methyl lithium,ethyl lithium, phenyl lithium, naphthyl lithium. The concentration ofthe alkyl or aryl lithium compound in the particular solvent usedamounts for example to from 5 to 30% by weight. The concentration of thebromothiophene or iodothiophene in the particular solvent amounts forexample to from 10 to 100% by weight.

In general, the bromothiophene or iodothiophene, either as such or inthe form of a solution in the ether or liquid aliphatic hydrocarbon orthe alkyl benzene, is added to the lithium alkyl or lithium aryl, whichis dissolved or suspended in one of the above-mentioned ethers or amixture of ether and aliphatic hydrocarbon in a volume ratio of 1-1.5:1or ether and alkylbenzene in a volume ratio of 0.2-0.5:1 (concentrationof the lithium compound from 5 to 30% by weight) and cooled to atemperature below -70° C., in such a way that the temperature does notexceed -70° C. The reaction component of formula (IV) is then added, forexample, in the form of a 10 to 100% solution (% by weight) in one ofthe above-mentioned dialkyl ethers or alkyl benzenes, again in such away that the temperature does not exceed -70° C.

In one preferred embodiment of the process according to the invention,the reaction is carried out in a solvent mixture of toluene anddiisopropyl ether and, after the reaction mixture has been hydrolyzed,the organic phase is subjected to a fractional vacuum distillation, thelow-boiling constituents of the mixture, such as for example diisopropylether, thiophene, butyl bromide, etc., together with some of the tolueneused being removed overhead, whilst a solution of 1,1-bis-[thien-(3)and/or thien-(2)-yl]-ω-halogen propanol in toluene is recovered as sumpresidue and is directly introduced into the next stage of the process.

The reactants may be used for example in the following molar ratios:thien-(3)-yl lithium:compound II=2.0-4.0:1.

Based on lithium alkyl and bromo- or iodothiophene, the following molarratio for example may be applied: alkyl lithiumcompound:3-bromo(iodo)thiophene:compound II=2.5-5.0:2.0-4.0:1, moreespecially 2.0-5.0:2.0-4.0:1.

The reaction temperature, for example, should not exceed -50° C. It isof advantage to carry out the reaction at a temperature of from -65° C.to -75° C., the reaction preferably being carried out at a temperaturebelow -70° C., for example at a temperature of from -80° C. to -70° C.

The 1,1-bis-[thien-(3 and/or 2)-yl]-ω-halogen propanol of formula (II)thus obtained may then be reacted with compound III directly, i.e.,without further purification. This reaction may be carried out in thepresence or absence of solvent or suspending agent. Suitable inertsolvents or suspending agents are, for example, the same solvents orsuspending agents which are used for the reaction of the thienyl lithiumwith compound IV, for example diisopropyl ether, toluene and the like.In addition, it is also possible for example to use other alkyl anddialkyl benzenes, dialkyl ethers, aliphatic ketones, e.g., acetone,methyl ethyl ketone, methyl butyl ketone, diethyl ketone and otherdialkyl ketones, and aliphatic or cycloaliphatic alcohols, e.g.,alkanols and cycloalkanols such as methanol, ethanol, isopropanol,propanol, butanol, hexanol, cyclohexanol.

It is also possible directly to react the reaction mixture, in which thecompound of formula (II) is formed, with compound III. Since a reactionmixture such as this still contains the alkyl halide formed during thereaction, it may be necessary to use a corresponding excess of compoundIII.

The derivatives obtained from the intermediate compound of formula (II)produced in accordance with the invention are substantially isomer-freeand are obtained in satisfactorily pure form after a singlecrystallization.

The compounds according to the invention are suitable for the productionof pharmaceutical compositions and preparations. The pharmaceuticalcompositions or medicaments contain, as active principle, one or more ofthe compounds according to the invention, optionally in admixture withother pharmacologically or pharmaceutically active substances. Themedicaments may be prepared with the usual pharmaceutical excipients,assistants, carriers and diluents.

As carriers and assistants, for example, are those recommended in thefollowing literature as adjuvants for pharmacy, cosmetic and relatedfields such as in Ullmann's Encyklopadie der technischer Chemie, Vol. 4(1953), pages 1 to 39; Journal of Pharmaceutical Sciences 52 (1963),pages 918 et seq.; N. v. Czetsch-Lindenwald, Hilftstoffe fur Pharmazieund angrenzende Gebiete; Pharm. Ind. 2 (1961), pages 72 et seq.; Dr. H.P. Fiedler, Lexicon der Hilftstoffe fur Pharmazie, Kosmetik undangrenzende Gebiete, Cantor Kg. Aulendorf i. Wurtt (1971).

Examples of such materials include gelatin, natural sugars such assucrose or lactose, lecithin, pectin, starch (for example cornstarch),alginic acid, tylose, talc, lycopodium, silica (for example colloidalsilica), glucose, cellulose, cellulose derivatives for example celluloseethers in which the cellulose hydroxyl groups are partially etherifiedwith lower aliphatic alcohols and/or lower saturated oxyalcohols (forexample, methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethylcellulose), stearates, e.g., methylstearate and glyceryl stearate,magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms,especially saturated acids (for example calcium stearate, calciumlaurate, magnesium oleate, calcium palmitate, calcium behenate andmagnesium stearate), emulsifiers, oils and fats, especially of plantorigin (for example, peanut oil, castor oil, olive oil, sesame oil,cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod-liveroil), mono-, di- and triglycerides of saturated fatty acids (C₁₂ H₂₄ O₂to C₁₈ H₃₆ O₂ and their mixtures), e.g., glyceryl monostearate, glyceryldistearate, glyceryl tristearate, glyceryl trilaurate), pharmaceuticallycompatible mono- or polyvalent alcohols and polyglycols such asglycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol,diethylene glycol, triethylene glycol, ethylene glycol, propyleneglycol, dipropylene glycol, polyethylene glycol 400 and otherpolyethylene glycols, as well as derivatives of such alcohols andpolyglycols, esters of saturated and unsaturated fatty acids (2 to 22carbon atoms, especially 10 to 18 carbon atoms), with monohydricaliphatic alcohols (1 to 20 carbon atom alkanols) or polyhydric alcoholssuch as glycols, glycerine, diethylene glycol, pentaerythritol,sorbitol, mannitol, ethyl alcohol, butyl alcohol, octadecyl alcohol,etc., e.g., glyceryl stearate, glyceryl palmitate, glycol distearate,glycol dilaurate, glycol diacetate, monoacetin, triacetin, glyceryloleate, ethylene glycol stearate; such esters of polyvalent alcohols canin a given case also be etherified, benzyl benzoate, dioxolane,glycerine formal, tetrahydrofurfuryl alcohol, polyglycol ethers with 1to 12 carbon atom alcohols, dimethyl acetamide, lactamide, lactates,e.g., ethyl lactate, ethyl carbonate, silicones (especially middleviscosity dimethyl polysiloxane), magnesium carbonate and the like.

For the production of solutions there can be used water orphysiologically compatible organic solvents, as for example, ethanol,1,2-propylene glycol, polyglycols, e.g., diethylene glycol, triethyleneglycol and dipropylene glycol and their derivatives, dimethyl sulfoxide,fatty alcohols, e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol andoleyl alcohol, triglycerides, e.g., glyceryl oleate, glyceryl stearate,glyceryl palmitate, and glyceryl acetate, partial esters of glycerine,e.g., monoacetic, diacetin, glyceryl monostearate, glyceryl distearate,glyceryl monopalmitate, paraffins and the like.

In the production of the preparations there can be used known andcustomary solution aids or emulsifiers. As solution aids and emulsifiersthere can be used, for example, polyvinyl pyrrolidone, sorbitan fattyacid esters such as sorbitan trioleate, lecithin, gum acacia, gumtragacanth, polyoxyethylated sorbitan monoleate, polyoxyethylated fats,polyoxyethylated oleotriglycerides, linolized oleotriglycerides,polyethylene oxide-condensation products of fatty alcohols, alkylphenolsor fatty acids. As used herein polyoxyethylated means that the materialsin question contain polyoxyethylene chains whose degree ofpolymerization generally is between 2 and 40, particularly between 10and 20.

Such polyoxyethylated materials for example can be obtained by reactionof hydroxyl group containing compounds (for example, mono- ordiglycerides) or unsaturated compounds such as, for example, thosecontaining the oleic acid radical with ethylene oxide (for example, 40moles of ethylene oxide per mole of glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, castor oil,sesame oil, cottonseed oil, corn oil (see also Dr. H. P. Fiedler, supra,pages 191-195).

Furthermore, there can be added preservatives, stabilizers, buffers, forexample, calcium hydrogen phosphate, colloidal aluminum hydroxide, tastecorrectives, antioxidants and complex formers (for example, ethylenediamine tetraacetic acid) and the like. In a given case forstabilization of the active molecule the pH is adjusted to about 3 to 7with physiologically compatible acids or buffers. Generally, there ispreferred as neutral as possible to weak acid (to pH 5) pH value. Asantioxidants there can be used for example sodium metal bisulfite,ascorbic acid, gallic acid, alkyl gallates, e.g., methyl gallate andethyl gallate, butyl hydroxyanisole, nordihydroguararetic acid,tocopherols as well as tocopherol and synergists (materials which bindheavy metals by complex formation, for example, lecithin, ascorbic acid,phosphoric acid). The addition of synergists increases considerably theantioxidant activity of tocopherol. As preservatives there can be usedfor example sorbic acid, p-hydroxybenzoic acid esters (for example,lower alkyl esters such as the methyl ester and the ethyl ester) benzoicacid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol,benzethonium chloride and formalin derivatives).

The pharmacological and galenical treatment of the compounds of theinvention takes place according to the usual standard methods. Forexample, the active material or materials and assistants or carriers arewell mixed by stirring or homogenization (for example, by means of acolloid mill or ball mill), wherein the operation is generally carriedout at temperatures between 20° and 80° C., preferably 20° to 50° C.

The application of active material or drug can take place on the skin ormucous membrane or internally, for example, orally, enterally,pulmonarily, rectally, nasally, vaginally, lingually, intravenously,intraarterially, intracardially, intramuscularly, intraperitoneally,intracutaneously or subcutaneously.

The addition of other medicines, especially cardiac glycosides,xanthines, retarders of the aggregation of thrombocytes, nicotinic acid,etc., is also possible or favorable.

The compounds of the invention on narcotized mongrel dogs showed astrong and persistent increase of the peripheral blood flow(circulation) which was determined with electromagnetic flow measuringapparatus. Simultaneously the heart time volume (cold dilution method)was noticeably increased. For example, with the above-mentioned testmethods at a dosage of 0.1 mg/kg body weight dog on the average duringone hour the circulation of the arteria femoralis increased about 47%.The heart time volume increased in the test on an hourly average about39%. This vasodilating activity is comparable to the activity of theknown medicine, Isoxsuprine.

The lowest vasodilating effective dosage in the above mentioned animalexperiment is 0.05 mg/kg intravenously, for example, 1 mg/kg orally;0.05 mg/kg intravenously.

As the general dosage range for the vasodilating activity (animalexperiments as above) there can be used for example 1 to 30 mg/kgorally, particularly 10 mg/kg, 0.1 to 3.0 mg/kg intraveously,particularly 0.3 mg/kg.

The compounds of the invention are indicated for use in disturbances ofthe peripheral circulation such as Morbus Raynaud, arteriosclerotic vasoillnesses, Ulcus cruris Claudicatio intermittent, diabetic angiopathy,apoplexy and post apoplectic conditions, old age conditioned tropicdisturbances as well as hypertonia, particularly in combination withdiuretica.

The pharmaceutical preparations generally contain between 5 to 50 mg ofthe active component or components of the invention.

The compounds can be delivered in the form of tablets, capsules, pills,dragees, plugs, salves, gels, creams, powders, dusts, aerosols or inliquid form. As liquid forms there can be used for example oily oralcoholic or aqueous solutions as well as suspension and emulsions. Thepreferred forms of use are tablets which contain between 10 and 50 mg orsolutions which contain between 1 and 5% of active material.

In individual doses the amount of active component of the invention canbe used for example in an amount of:

a. in oral dispensation between 10 and 50 mg;

b. in parenteral dispensation (for example intravenously,intramuscularly) between 5 and 20 mg;

c. in dispensation by inhaling (solutions or aerosols) between 3 and 10mg.

For example, there is recommended the use of 1 to 3 tablets containing20 and 100 mg of active ingredient 3 times daily or for example,intravenously the injection 1 to 3 times daily of a 1 to 10 ml ampoulecontaining 3 to 30 mg of active substance. In oral preparations theminimum daily dosage for example is 50 mg; the maximum daily dosage inoral administration should not be over 2 grams.

The dosages in each case are based on the free base.

In veterinary medicine the compounds of the invention can be used intreating dogs and cats. The individual dosages in general orally arebetween approximately 5 and 20 mg/kg body weight; the parenteral dosageapproximately between 0.3 and 1.0 mg/kg body weight.

The acute toxicity of the compounds of the invention in the mouse(expressed by the LD₅₀ mg/kg method of Miller and Tainter, Proc. Soc.Exper. Biol. and Med. 57 (1944), pages 261 et seq.) in oral applicationis between 200 mg/kg and 800 mg/kg, in some cases even above 1000 mg/kg.

The drugs can be used in human medicine, in veterinary medicine as wellas in agriculture alone or in admixture with other pharmacologicallyactive materials.

Unless otherwise indicated all parts and percentages are by weight.

The compositions can comprise, consist essentially of or consist of thematerials set forth.

The methods can comprise, consist essentially of or consist of the stepsset forth with the materials shown.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is illustrated by the following Examples.

EXAMPLE 1[1,1-Dithien-(3)-yl-1-hydroxy-(3)-propyl]-[1-hydroxy-1(p-hydroxyphenyl)-(2)-propyl]-amine

25 g (0.15 mole) of p-hydroxy norephedrine, 22.5 ml of triethylamine and45.5 g (0.15 mole) of 1,1-dithien-(3)-yl-3-bromo-(1)-propanol wereheated with stirring for 8 hours to 100° C. in 80 ml of dioxane. Themixture was then largely concentrated in a rotary evaporator, 150 ml ofwater were added to the residue which was then extracted by shakingthree times with 100 ml of diethyl ether. The combined ethereal extractsare dried with magnesium sulfate. After a few hours at 0° C., a palecolored substance crystallized out and was recrystallized from acetone.15 g of colorless crystalline substance were obtained. M.P.: 174°-175°C.

Hydrogen Maleate

To prepare this salt, 5.0 g of the base were suspended in 30 ml ofethylacetate. Following the addition of 1.5 g of maleic acid, a clearsolution was formed to which diethyl ether was added until it just beganto cloud. After standing for 12 hours, the crystallizate was filteredoff under suction, washed with ethylacetate and dried: yield 4.0 g ofhydrogen maleate. M.P.: 108°-109° C.

Production of the corresponding starting material1,1-dithien-(3)-yl-3-bromo-(1)-propanol

In a 1.5 liter four-necked flask equipped with a dropping funnel, adrying tube, a stirrer, a thermometer and an inlet for nitrogen, 300 mlof absolute diisopropyl ether were cooled under nitrogen with a coolingbath of methanol and dry ice. During cooling, a 15% solution of 335.2 mlof n-butyl lithium in hexane (0.55 mole) was added and the mixturecooled to -75° C. A solution of 81.5 g of 3-bromothiophene (0.5 mole) in100 ml of absolute diisopropyl ether was then added dropwise over aperiod of 90 minutes in such a way that a temperature of -70° C. was notexceeded. The reaction mixture was then left to after react for 1 hourat -70° C. to -75° C. A solution of 36.2 g of β-bromopropionic acidethyl ester (0.2 mole) in 60 ml of absolute diisopropyl ether was thenadded dropwise over a period of 90 minutes in such a way that thetemperature of -70° C. was not exceeded. The reaction mixture was thenleft to after react for another 4 hours. The cooling bath was thenremoved and 160 ml of water were added to the reaction mixture. Thetemperature rises to -20° C. The reaction mixture was then stirred for awhile until the temperature had risen above 0° C., after which theorganic phase was separated off, dried with MgSO₄, filtered and all thelow-boiling constituents are distilled off in vacuo in a rotaryevaporator. A light oil was obtained as residue. Yield: 54 g (96% of thetheoretical, based on the bromopropionic acid ester).

In the same manner there were obtained1,1-dithienyl-(3)-4-bromo-butanol-(1) and1,1-dithienyl-(3)-5-bromo-pentanol-(1) in the form of light oils.

EXAMPLE 2 ##STR57##

The solution of 16.2 g (0.1 mole) of 4-phenyl piperazine, 14 ml oftriethylamine and 31.7 g (0.1 mole) of1,1-dithienyl-(3)-1-hydroxy-4-bromobutane in 80 ml of diisopropyl etherwas allowed to stand for 3 days at room temperature. The crystallineproduct was filtered off with suction, washed with ether, dried, stirredin water, filtered off with suction, washed with water and dried. Thecrude yield was 24.4 g, 61.3%.

8 g (0.02 mole) of the crude base were dissolved in 50 ml of acetone.After addition of an acetone solution containing 2.32 g (0.02 mole) ofmaleic acid, heating and filtering ether was added to the beginning ofturbidity. After a short time the material crystallized. This wasfiltered off with suction, washed with acetone/ether (1:1 by volume) anddried. Yield: 8.3 g (81%). M.P. of the maleate 110°-111° C.

EXAMPLE 31,1-Dithienyl-(3)-1-hydroxy-4-[4-(3-methoxyphenyl)-piperazino]butane

This compound was obtained in an analogous manner to Example 2 using 0.1mole of 4-(3-methoxyphenyl)-piperazine. M.P. of the maleate: 149°-150°C. (Yield 94%).

EXAMPLE 4 1,1-Dithienyl-(3)-1-hydroxy-5-dimethyl-amino-pentane

The solution of 33 g (0.72 mole) of dimethylamine in 100 ml of benzeneand 33.1 g (0.1 mole) of 1,1-dithienyl-(3)-1-hydroxy-5-bromopentane wasallowed to stand in a closed reaction vessel for 10 days at roomtemperature.

Then the crystal mass was filtered off with suction and dried. Afterconcentration of the solution and addition of ether to the residue thecrystalline product precipitated out. This was filtered off withsuction, dried, combined with the first product obtained and thenslurried in water, filtered off with suction, washed with water anddried.

The crude yield was 23.3 g (78%). M.P. 129°-130° C.

10 g of base (0.0338 mole) were slurried in 30 ml of acetone. Afteraddition of 4 g of maleic acid there was formed a clear solution. Etherwas added to the beginning of turbidity whereupon after 3 days thesubstance crystallized.

After filtering off with suction, washing with acetone/ether (1:1 byvolume) and drying there were obtained 11.5 g (82% of the titlematerial) of the maleate of the title material, M.P. 79°-80° C.

EXAMPLE 5

Production of Addition [1,1-Dithienyl-(3)-1-hydroxypropyl-(3)]amines ofthe Formula ##STR58##

The meaning of --NHY is given in Table 1 column 2.

The compounds entered in Table 1 were produced according to thefollowing procedure:

0.1 mole of 1,1-dithienyl-(3)-3-bromopropanol-(1), 0.11 mole oftriethylamine and 0.1 mole of primary or secondary amine (see column 2of Table 1) were heated at reflux in 60 ml of diisopropyl ether forabout 12-15 hours with stirring. After cooling the crystallizate wasfiltered off with suction, washed with diisopropyl ether and dried. Thenit was slurried in water, filtered off with suction, washed with water,dried, recrystallized and analogous to Example 1 there was optionallyproduced the maleic acid salt.

                                      Table 1                                     __________________________________________________________________________                                      Solvent from Which                                                                      M.P. of the                       Compound                          the Salt was                                                                            Salt or Base                      No. D Amine Component NHY  Salt   Recrystallized                                                                            (°C.)                                                                       Yield                      __________________________________________________________________________                                                       (%)                        13564                                                                                ##STR59##           Maleate                                                                              Ethanol/Ether                                                                           140°-141°                                                              51                         13633                                                                                ##STR60##           Bis-hydrogen- maleate                                                                Ethanol/Ether                                                                           180°-181°                                                              42                         13632                                                                                ##STR61##           Bis-hydrogen- maleate                                                                Ethanol/Ether                                                                           186°-187°                                                              45                         13637                                                                                ##STR62##           Maleate                                                                              Methanol/Ether                                                                          130°-131°                                                              39.9                       13774                                                                                ##STR63##           Bis-hydrogen- maleate                                                                Methanol  179°-180°                                                              38.6                       13834                                                                                ##STR64##           Maleate                                                                              Acetone   154°-155°                                                              23                         13864                                                                                ##STR65##           Bis-hydrogen- maleate                                                                Acetone/Ether                                                                           140°-142°                                                              35                         13895                                                                                ##STR66##           Bis-hydrogen- maleate                                                                Methanol  154°-155°                                                              27                         13941                                                                                ##STR67##           Maleate                                                                              Methanol  204°-206°                                                              31.5                       14020                                                                                ##STR68##             --   Methanol  165°-166°                                                       (Base) 42                         14055                                                                                ##STR69##           Bis-hydrogen- maleate                                                                Isopropanol                                                                             144°-150°                                                              25                         14068                                                                                ##STR70##           Maleate                                                                              Acetone   147°-150°                                                              47                         __________________________________________________________________________

EXAMPLE 6[1,1-Dithien-(3)-yl-1-propen-(3)-yl]-[1-hydroxy-1-(p-hydroxyphenyl)-(2)-propyl]-amine

25 g (0.15 mole) of p-hydroxy norephedrine, 22.5 ml of triethylamine and45.5 g (0.15 mole) of 1,1-dithien-(3)-yl-3-bromo-(1)-propanol wereheated with stirring for 8 hours to 100° C. in 80 ml of dioxane. Themixture was then substantially concentrated in a rotary evaporator andthe syrupy residue was digested twice with 250 ml of diethyl ether. Thecombined ethereal solutions were acidified with isopropanolic HCl, as aresult of which a highly viscous product precipitated. After the solventwas poured off, the residue was taken up in 100 ml of ethanol, followedby boiling under reflux for 10 minutes. The solution was thenconcentrated in a rotary evaporator. The residue was dissolved in 100 mlof warm acetone from which the substance slowly crystallized out aftercooling. Recrystallization from isopropanol gave the hydrochloride ofthe compound in the form of colorless crystals. M.P. of thehydrochloride: 138°-140° C. Yield: 10.2 g.

EXAMPLE 7

Production of 1,1-Dithienyl-(3)-alken-(1)-yl-amines of the Formula##STR71##

The meanings of NHY and Alk are given in Table 2.

The compounds entered in Table 2 were produced according to thefollowing procedure:

0.1 mole of an amine of the formula ##STR72## (the meanings of NHY andAlk are given in Table 2) was dissolved in 50 ml of methanol and treatedwith a 10% excess of the amount necessary to form the salt ofisopropanolic hydrochloric acid whose concentration was 5-7 moles perliter. The reaction mixture was heated for about 20-30 minutes underreflux. After cooling the various compounds crystallized out. If thisoccasionally is not the case then the solutions are treated withsufficient ether that a lasting turbidity occurs; the reaction productthere separates out, usually in crystalline form.

The solvents for recrystallization are preferably methanol, ethanol andisopropanol.

                                      Table 2                                     __________________________________________________________________________                                          Solvent from Which                      Compound                              the Salt was                                                                            M.P. of the                   No. D Amine Component NHY  Alk    Salt                                                                              Recrystallized                                                                          Salt (°C.)                                                                     Yield                 __________________________________________________________________________                                                            (%)                   13565                                                                                ##STR73##           CH.sub.2                                                                             2 HCl                                                                             Methanol (Ether)                                                                        215°-217°                                                       decomposition                                                                         78.8                  13631                                                                                ##STR74##           CH.sub.2                                                                             2 HCl                                                                             Methanol  188°-189°                                                       decomposition                                                                         85.5                  13630                                                                                ##STR75##           CH.sub.2                                                                             2 HCl                                                                             Isopropanol                                                                             218°-219°                                                               71.9                  13629                                                                                ##STR76##           CH.sub.2                                                                             2 HCl                                                                             Methanol  215°-216°                                                               40                    13635                                                                                ##STR77##           CH.sub.2                                                                             2 HCl                                                                             Methanol  244°-245°                                                               90.4                  13634                                                                                ##STR78##           CH.sub.2                                                                             2 HCl                                                                             Methanol  270° (decomposition                                                    )       98                    13636                                                                                ##STR79##           CH.sub.2                                                                             2 HCl                                                                             Methanol  228°-229°                                                               33                    13719                                                                                ##STR80##           CH.sub.2                                                                             2 HCl                                                                             Methanol  194°-195°                                                               42                    13724                                                                                ##STR81##           CH.sub.2                                                                             2 HCl                                                                             Methanol  220° decomposition                                                             63                    13737                                                                                ##STR82##            CH.sub.2                                                                            2 HCl                                                                             Methanol/Ether                                                                          185°-187°                                                               54                    13833                                                                                ##STR83##           CH.sub.2                                                                             2 HCl                                                                             Isopropanol/Ether                                                                       160°-161°                                                               65                    13835                                                                                ##STR84##           CH.sub.2                                                                             HCl Isopropanol/Ether                                                                       142°-143°                                                               56                    13863                                                                                ##STR85##           CH.sub.2                                                                             HCl Isopropanol/Ether                                                                       169°-170°                                                               90                    13866                                                                                ##STR86##           CH.sub.2                                                                             2 HCl                                                                             Isopropanol/Ether                                                                       145°-146°                                                               78.5                  13897                                                                                ##STR87##           CH.sub.2                                                                             HCl Methanol/Ether                                                                          137°-138°                                                               72                    14003                                                                                ##STR88##           CH.sub.2                                                                             3 HCl                                                                             Methanol  250°-252°                                                               56                    14057                                                                                ##STR89##           CH.sub.2                                                                             HCl Methanol  204°-207°                                                       decomposition                                                                         48.5                  14094                                                                                ##STR90##           CH.sub.2                                                                             HCl Isopropanol/Ether                                                                       188°-191°                                                               67                    13661                                                                                ##STR91##           (CH.sub.2).sub.2                                                                     HCl Ethanol/Ether                                                                           182°-183°                                                               46.9                  13662                                                                                ##STR92##           (CH.sub.2).sub.2                                                                     HCl Ethanol/Ether                                                                           175°-176°                                                               38                    13678                                                                                ##STR93##           (CH.sub.2).sub.2                                                                     HCl Methanol/Ether                                                                          183°-184°                                                               15                    13685 NHCH.sub.3           (CH.sub.2).sub.2                                                                     HCl Acetone/Ether                                                                           155°-156°                                                               35                    13682                                                                                ##STR94##           (CH.sub.2).sub.2                                                                     2 HCl                                                                             Methanol/Ether                                                                          212°-213°                                                               30                    13686                                                                                ##STR95##           (CH.sub.2).sub.2                                                                     2 HCl                                                                             Methanol  216°-217°                                                       decomposition                                                                         49                    13705                                                                                ##STR96##           (CH.sub.2).sub.2                                                                     HCl Methanol/Ether                                                                          143°-144°                                                               59                    13800                                                                                ##STR97##           (CH.sub.2).sub.2                                                                     HCl Methanol  210°-211°                                                               68                    13775                                                                                ##STR98##           (CH.sub.2).sub.3                                                                     HCl Ethanol   191°-192°                                                               26                    13786                                                                                ##STR99##           (CH.sub.2).sub.3                                                                     2 HCl                                                                             Methanol/Ether                                                                          203°-204°                                                       decomposition                                                                         28                    13799                                                                                ##STR100##          (CH.sub.2).sub.3                                                                     2 HCl                                                                             Methanol  225°-226°                                                       decomposition                                                                         28                    13861                                                                                ##STR101##          (CH.sub.2).sub.3                                                                     HCl Methanol/Ether                                                                          177°-178°                                                               15                    __________________________________________________________________________

EXAMPLE 8 (CAPSULES)

To prepare 500,000 capsules there were required the following rawmaterials:

    ______________________________________                                        I.   D 13565 compound (see Table 2)                                                                      10.0 kg                                                 Lactose               60.0 kg                                                 Microcrystalline cellulose                                                                          58.8 kg                                                 Magnesium stearate    1.2 kg                                                                       130.0 kg                                            II.  500,000 gelatin capsules, size 2                                         ______________________________________                                    

Production

(1) D 13565 compound was comminuted to such an extent in an air jet millequipped with a dust shield that the particles had the followingparticle size:

at least 50%--not over 5μ

the remainder--not over 10μ

This comminuted compound is identified below as micronized D 13565compound.

(2) The total raw materials which were necessary for production of thecapsule composition were passed through a sieve having a mesh width of1.5 mm. Then 58.8 kg of micronized cellulose and 10 kg of micronized D13565 compound were mixed for 1 hour at 10 revolutions per minute in aTurbula mixer. Subsequently, the mixture was treated with 60 kg oflactose and 1.2 kg of magnesium stearate and again mixed for 45 minutes.This composition is called the capsule filling composition.

(3) The capsule filling composition was filled into gelatin capsules ofsize 2.

Amount of filling per capsule: 260 mg.

EXAMPLE 9 (SUPPOSITORIES) Production

20 g of D 13565 compound were worked into 1980 g of molten suppositorycomposition (for example, hard fat DAB 7) and in known manner poured outin forms for 2.0 g suppositories.

1 suppository contains 20 mg of D 13565 compound.

What is claimed is:
 1. A compound of the formula: ##STR102##where >A--B-- has either the structure >C(OH)--CH₂ or thestructure >C═CH, Alk is a C₁ -C₅ -alkylene group and NYH is ##STR103##where R' is hydrogen; phenyl; phenyl substituted once or twice by C₁ -C₄-alkyl groups, C₁ -C₄ -alkoxy groups or by halogen atoms; a C₁ -C₆-alkyl group; a C₁ -C₄ -hydroxyalkyl group; or a phenalkyl group whosealkyl portion consists of 1-4 carbon atoms or such a phenalkyl groupcontaining 1 to 3 C₁ -C₄ -alkoxy group substituents and salts thereof.2. A compound according to claim 1 in the form of the free base.
 3. Acompound according to claim 1 in the form of a pharmaceuticallyacceptable addition salt.
 4. A compound according to claim 1wherein >A--B-- is >C(OH)--CH₂ --.
 5. A compound according to claim 1wherein >A--B-- is >C═CH--.
 6. A compound according to claim 1 whereinAlk is a straight chain alkylene group of 1 to 3 carbon atoms.
 7. Acompound according to claim 1 wherein Alk is a straight chain alkylenegroup of 1 to 3 carbon atoms.
 8. A compound according to claim 7 whereinR' is phenyl, 1 to 2 carbon atom alkylphenyl or 1 to 2 carbon atomalkoxyphenyl.
 9. A compound according to claim 8 wherein R' is phenyl.10. A compound according to claim 8 wherein R' is o-methylphenyl,o-ethylphenyl, o-methylphenyl or o-ethoxyphenyl.
 11. A compoundaccording to claim 7 wherein R' is benzyl or phenethyl.
 12. A medicamentcontaining as an active ingredient in an amount sufficient to increaseblood circulation a compound of claim 1 together with a pharmaceuticalexcipient or diluent.
 13. A method of increasing blood circulation in amammal comprising administering to the mammal in an effective amount ofa compound of claim 1 to increase the blood circulation.
 14. A methodaccording to claim 13 wherein the compound is administered orally.
 15. Amethod according to claim 14 wherein there is administered orally atleast 1 mg/kg body weight of the mammal.
 16. A method according to claim13 wherein the compound is administered intravenously.
 17. A methodaccording to claim 13 wherein there is administered intravenously atleast 0.05 mg/kg body weight of the mammal.
 18. A compound according toclaim 1 where R¹ is phenyl, phenyl substituted with 1 to 2 methoxygroups, benzyl or benzyl substituted with 1 to 3 methoxy groups.
 19. Acompound according to claim 18 wherein A is attached to both thienylgroups in the 3 positions.
 20. A compound according to claim 19 whereinA--B is >C═CH.
 21. A compound according to claim 20 where Alk is CH₂ andR¹ is 2,4-trimethoxybenzyl.
 22. A compound according to claim 20 whereAlk is CH₂ and R¹ 2,3-dimethoxybenzyl.
 23. A compound according to claim20 where Alk is --Ch₂ CH₂ -- and R¹ is 2-methoxyphenyl.
 24. A compoundaccording to claim 20 wherein Alk is --(CH₂)₃ -- and R¹ is phenyl.
 25. Acompound according to claim 18 wherein A--B is >C═CH.